1. Flow of study selection and descriptives

The flow of study selection is shown in Figure 1. Studies included were published between 1991 and 2023. Overall, this analysis includes 29 studies containing 166 comparisons.

Figure 1

Table 1 below gives a summary of the included studies for the effect of model induction. N represents an aggregate of animals contributing to outcomes reported from control and treatment groups, and if the same control group has contributed to more than one experiment, those animals will be counted more than once.

Study Model Strain Outcome N
AMIRI, 2016 maternal separation NMRI Sucrose preference test 24
BORGES, 2013 iuGC Wistar (rat) DOPAC concentration 20
~ ~ ~ Dopamine concentration 20
~ ~ ~ Sucrose preference test 14
BROCCO, 2006 CMS Wistar (rat) Sucrose preference test 48
CARRATALA, 2023 Tetrabenzine CD-1 (mouse) Sucrose preference test 132
EREN, 2007 CMS Wistar (rat) Sucrose preference test 16
EREN, 2014 CUMS Wistar (rat) Sucrose preference test 16
FATIMA, 2020 PNS Wistar (rat) Dopamine receptor biology 24
~ ~ ~ Sucrose preference test 12
JIANG, 2014 Defeat C57BL/6J (mouse) Sucrose preference test 100
KOO, 2018 MCAO C57BL/6 (mouse) Sucrose preference test 36
KRUPINA, 1995 MPTP Wistar (rat) Sucrose preference test 12
MUSCAT, 1992 CMS Lister hooded (rat) Sucrose preference test 20
OSACKA, 2022 CMS Sprague-dawley (rat) Sucrose preference test 21
PAPP, 1993 CUMS Lister hooded (rat) Sucrose preference test 32
PAPP, 1994 CMS Wistar (rat) Dopamine receptor biology 160
~ ~ ~ Sucrose preference test 20
PAPP, 1996 CUMS Wistar (rat) Sucrose preference test 20
~ CUMS 2 ~ ~ 16
QIAO, 2020 CUS Sprague-dawley (rat) Dopamine concentration 24
~ ~ ~ Dopamine receptor biology 24
~ ~ ~ Sucrose preference test 24
RANA, 2014 CMS Swiss albino Sucrose preference test 12
STAMFORD, 1991 CUMS Lister hooded (rat) Dopamine concentration 72
~ ~ ~ Sucrose preference test 18
TAN, 2015 TBI Sprague-dawley (rat) DOPAC concentration 15
~ ~ ~ Dopamine concentration 15
~ ~ ~ Sucrose preference test 15
TOMAZ, 2020 LPS Wistar (rat) Sucrose preference test 16
WANG, 2021 CUS C57BL/6 (mouse) Sucrose preference test 16
WEI, 2021 CMS C57BL/6J (mouse) Sucrose preference test 12
WILLNER, 1994 CUMS PVG Hooded Sucrose preference test 44
WU, 2014 CUMS Sprague-dawley (rat) Sucrose preference test 12
YAN, 2022 CUMS Sprague-dawley (rat) DA/DOPC ratio 60
~ ~ ~ Dopamine concentration 60
~ ~ ~ Sucrose preference test 20
YU, 2016 CUS Wistar (rat) Sucrose preference test 12
YUAN, 2011 CUMS Sprague-dawley (rat) Sucrose preference test 17
ZHAO, 2018 CMS Sprague-dawley (rat) Sucrose preference test 20

Abbreviations

iuGC - intra-uterine glucocorticoid: CMS - chronic mild stress: CUMS - chronic unpredictable mild stress: CUS - chronic unpredicatble stress: PNS - prenatal stress: Defeat - social defeat stress: TBI - traumatic brain injury: LPS - intraperitoneal lipopolysaccharide: MCAO - middle cerebral artery occlusion: WAG/Rij = genetic model of absence epilepsy with co-morbid depression

Table 2 below gives a summary of the included studies for the effect of dopaminergic interventions. N represents an aggregate of animals contributing to outcomes reported from control and treatment groups, and if the same control group has contributed to more than one experiment, it will be counted twice.While some authors considered imipramine to have dopaminergic effects, we considered, given that this was a minor contribution to its pharmacological repertoire, that these studies should not be included in this iteration of the review.

Study Model Strain Comparison Outcome N
AMIRI, 2016 maternal separation NMRI selegiline, 1 mg/kg Sucrose preference test 12
~ ~ ~ selegiline, 3 mg/kg Sucrose preference test 24
~ ~ ~ selegiline, 5 mg/kg Sucrose preference test 12
BORGES, 2013 iuGC Wistar (rat) L-DOPA, 24 mg/kg DOPAC concentration 20
~ ~ ~ L-DOPA, 24 mg/kg Dopamine concentration 20
~ ~ ~ L-DOPA, 24 mg/kg Sucrose preference test 14
BROCCO, 2006 CMS Wistar (rat) piribedil, 2.5 mg/kg Sucrose preference test 16
~ ~ ~ piribedil, 10 mg/kg Sucrose preference test 16
~ ~ ~ piribedil, 40 mg/kg Sucrose preference test 16
CARRATALA, 2023 Tetrabenzine CD-1 (mouse) buproprion, 10 mg/kg Sucrose preference test 132
EREN, 2007 CMS Wistar (rat) aripiprazole, 2.5 mg/kg Sucrose preference test 16
EREN, 2014 CUMS Wistar (rat) aripiprazole, 2.5 mg/kg Sucrose preference test 16
FATIMA, 2020 PNS Wistar (rat) ropinirole, 10 mg/kg Dopamine receptor biology 24
~ ~ ~ ropinirole, 10 mg/kg Sucrose preference test 12
JIANG, 2014 Defeat C57BL/6J (mouse) SKF83959, 0.5 mg/kg Sucrose preference test 20
~ ~ ~ SKF83959, 1 mg/kg Sucrose preference test 100
KOO, 2018 MCAO C57BL/6 (mouse) aripiprazole, 1 mg/kg Sucrose preference test 36
KRUPINA, 1995 MPTP Wistar (rat) bromocriptine, 5 mg/kg Sucrose preference test 12
MUSCAT, 1992 CMS Lister hooded (rat) quinpirole, 200 ug/kg Sucrose preference test 20
OSACKA, 2022 CMS Sprague-dawley (rat) aripiprazole, 10 mg/kg Sucrose preference test 22
PAPP, 1993 CUMS Lister hooded (rat) quinpirole, 100 ug/kg Sucrose preference test 24
~ ~ ~ quinpirole, 200 ug/kg Sucrose preference test 24
~ ~ ~ quinpirole, 400 ug/kg Sucrose preference test 24
PAPP, 1996 CUMS Wistar (rat) D-amphetamine, 0.5 mg/kg Sucrose preference test 20
~ CUMS 2 Wistar (rat) D-amphetamine, 1.5 mg/kg Sucrose preference test 16
QIAO, 2020 CUS Sprague-dawley (rat) dopamine, 3.83 ug Sucrose preference test 24
~ ~ ~ quinpirole, 0.877 ug Sucrose preference test 24
RANA, 2014 CMS Swiss albino bromocriptine, 2 mg/kg & simvastatin, 10 mg/kg Sucrose preference test 12
~ ~ ~ L-DOPA, 200 mg/kg & simvastatin, 10 mg/kg Sucrose preference test 12
~ ~ ~ simvastatin, 10 mg/kg Sucrose preference test 12
RUSSO, 2013 WAG/Rij rat WAG/Rij aripiprazole, 0.3 mg/kg Sucrose preference test 20
~ ~ ~ aripiprazole, 1 mg/kg Sucrose preference test 20
~ ~ ~ aripiprazole, 3 mg/kg Sucrose preference test 20
TAN, 2015 TBI Sprague-dawley (rat) amantadine, 45 mg/kg DOPAC concentration 14
~ ~ ~ amantadine, 45 mg/kg Dopamine concentration 14
~ ~ ~ amantadine, 45 mg/kg Sucrose preference test 14
~ ~ ~ amantadine, 135 mg/kg DOPAC concentration 14
~ ~ ~ amantadine, 135 mg/kg Dopamine concentration 14
~ ~ ~ amantadine, 135 mg/kg Sucrose preference test 14
TOMAZ, 2020 LPS Wistar (rat) tranylcypromine, 10 mg/kg Sucrose preference test 16
WANG, 2021 CUS C57BL/6 (mouse) cryptotanshinone, 20 mg/kg Sucrose preference test 16
WEI, 2021 CMS C57BL/6J (mouse) pramipexole, 1 mg/kg Sucrose preference test 12
WILLNER, 1994 CUMS PVG Hooded pramipexole, 1 mg/kg Sucrose preference test 88
~ ~ PVG Hooded pramipexole, 2 mg/kg Sucrose preference test 88
WU, 2014 CUMS Sprague-dawley (rat) SKF38393, 1.12 ug Sucrose preference test 12
YAN, 2022 CUMS Sprague-dawley (rat) P. orientalis seed, 10 mg/kg DA/DOPC ratio 60
~ ~ ~ P. orientalis seed, 10 mg/kg Dopamine concentration 60
~ ~ ~ P. orientalis seed, 10 mg/kg Sucrose preference test 20
~ ~ ~ P. orientalis seed, 33 mg/kg DA/DOPC ratio 60
~ ~ ~ P. orientalis seed, 33 mg/kg Dopamine concentration 60
~ ~ ~ P. orientalis seed, 33 mg/kg Sucrose preference test 20
~ ~ ~ P. orientalis seed, 100 mg/kg DA/DOPC ratio 60
~ ~ ~ P. orientalis seed, 100 mg/kg Dopamine concentration 60
~ ~ ~ P. orientalis seed, 100 mg/kg Sucrose preference test 20
YU, 2016 CUS Wistar (rat) amantadine, 25 mg/kg Sucrose preference test 12
YUAN, 2011 CUMS Sprague-dawley (rat) SKF38393, 1.12 ug/kg Sucrose preference test 16
ZHAO, 2018 CMS Sprague-dawley (rat) 2_HBC, 2.5 mg/kg Sucrose preference test 20
~ ~ ~ 2_HBC, 10 mg/kg Sucrose preference test 20
~ ~ ~ buproprion, 2.5 mg/kg Sucrose preference test 20

References of included studies are located in the appendix. Included studies used 30 unique disease model induction procedures.

1.1 Description of experiment types and methodological approach

Within the literature we identified distinct categories of experiments and the data presented would allow several meta-analytic contrasts to be drawn:

Effects of disease modelling. These are experiments investigating the effect of models of depression, reported in 74 experiments from 28 publications.

In these studies the:

  • Control group is a group of animals that is (1) not subjected to a depression model induction paradigm and (2) is administered a control treatment (vehicle) or no treatment.

  • Intervention group is a group of animals that is (1) subjected to a depression model induction paradigm and (2) is administered a control treatment (vehicle) or no treatment.

Treatment vs control. These were experiments investigating the effect of administering a dopaminergic agent, reported in 92 experiments from 27 publications.

In these studies the:

  • Control group is a group of animals that is (1) subjected to a depression model induction paradigm and (2) administered a control treatment (vehicle) or no treatment.

  • Intervention group is a group of animals that is (1) subjected to a depression model induction paradigm and (2) administered a TAAR1 agonist treatment.

  • Sham group is a group of animals that is (1) not subjected to a depression model induction paradigm and (2) administered a control treatment (vehicle) or no treatment. These data are required to allow a ‘normalised mean difference’ effect size to be calculated, given by

\[ \frac{{\bar{\mu}_C - \bar{\mu}_T}}{{\bar{\mu}_C - \bar{\mu}_S}} \times 100 \]

where \(\bar{\mu}_C\), \(\bar{\mu}_T\), \(\bar{\mu}_S\) are the mean reported scores in the control, treatment, and sham groups respectively.

Outcomes with ≥2 independent effect sizes were considered for meta-analysis. In this iteration of the review, this includes sucrose preference test, dopamine concentration, dopamine receptor biology and dopac concentration.

All analyses were conducted allowing for the following hierarchical levels in a random effects model, which accounts for features common to experimental contrasts such as a shared control group:

  • Level 1: Rodent strain - effect sizes measured across experiments using the same rodent strain.

  • Level 2: Study - effect sizes measured from different experiments presented in the same publication.

  • Level 3: Experiment - effect sizes measured in the same experiment within a study, where often a control group contributes to several effect sizes.

Each level for the hierarchy was only included in the model if more than 4 categories were present for at least one of these levels. Where more than 4 categories are not present for all levels, the variance attributable to that level is reported as zero.

The hierarchical grouping may therefore be considered thus: Strains of laboratory animals are included in several Studies, each of which can report one or more Experiments, and each Experiment is comprised of at least two Cohorts which are considered identical except for differing in the experimental manipulation (the Intervention) or not being exposed to the disease modelling procedures (a Sham cohort, these only being used to provide a baseline for outcome measures to allow Normalised Mean Difference meta-analysis). An Experiment can include several experimental contrasts, for instance where different doses of drugs are compared to the same control group.

We constructed multilevel models without Knapp-Hartung adjustments as these are not available for rma.mv class objects in the metafor package. Instead, the model is set to test = "t" to use t- and F-distributions for making inferences, and dfs="contain" to improve the method of approximating degrees of freedom of these distributions.

The scales and units used to measure outcomes in preclinical studies often differ between studies although they may measure the same underlying biological construct. The primary effect size used for meta-analysis of preclinical studies is therefore the standardised mean difference (SMD, Hedge’s g). For experiments testing the effects of interventions we also present a sensitivity analysis using normalised mean difference (NMD), where there are sufficient data for sham procedures to allow this. This analysis is not possible for studies of the effect of modelling depression.

For some experimental contrasts, more than one outcome of the same category - for instance dopamine concentrations in different brain regions - was measured in the same cohort of animals. Sometimes, sucrose preference tests were performed in the same cohort at different times. Some publications used the same drug doses with the same outcome measures in independent experiments. For these reasons, some of the forest plots may appear to include ‘duplicate’ Study - Drug - Dose combinations with different outcomes. For the later, these are accounted for in the hierarchical analysis, but for the former there were insufficient levels of the different outcome category measured to allow for hierarchical analysis and so this was not performed.

2 Dopaminergic agent v Control

These experiments test the effect of dopaminergic agents on outcome in animals which have been exposed to a ‘modelling intervention’ intended to recapitulate some features of human depression. Modelling interventions comprise behavioural (47 experiments), genetic (3), pharmacological (9) and surgical (5) approaches. Outcomes include ‘apical’ endpoints (sucrose preference test), and also endpoints which might be considered intermediate, and may give insights to the mechanisms through which apical effects occur. These include concentrations of dopamine and DOPAC (an active metabolite of dopamine) and the ratio between these; and observed changes in dopamine receptor biology.

27 studies (92 comparisons) investigated the effects of dopaminergic agents versus Control. The number of studies and individual effect sizes for each outcome were:

* This outcomes was identified in the study protocol as primary outcomes of interest.

2.1 Outcome 1: Sucrose preference

2.1.1 Risk of bias

Figure 2.1.1 shows the risk of bias traffic light plot for studies investigating the effect of administering a dopaminergic agent on Sucrose preference in animals. The risk of bias assessment was performed using the SyRCLE RoB tool.

Figure 2.1.1

2.1.2 Reporting completeness

Figure 2.1.2 shows the reporting completeness traffic light plot for studies investigating the effect of administering a dopaminergic agent on Sucrose preference in animals. The reporting completeness assessment was performed using the ARRIVE guidelines.

Figure 2.1.2

2.1.3 Meta-analysis

The effect of administering a dopaminergic agent on Sucrose preference in animals using SMD as the effect size is shown in Figure 2.1.3. The pooled estimate for SMD across all individual comparisons is displayed as a diamond shape at the bottom of the plot. Dotted lines indicate the prediction interval of the pooled estimate.

Figure 2.1.3

Dopaminergic agents had a pooled effect on Sucrose preference of SMD = 1.335 (95% CI: 0.878 to 1.792; 95% PrI: -0.756 to 3.426).

64 experimental comparisons were reported in 36 experiments reported from 27 publications and involving 10 different animal strains.

Level Number of categories for that level included in this analysis Attributable variance
Strain 10 0
Study x Strain 27 0.803
Study x Strain x Experiment 36 0.01

2.1.4 Subgroup analyses and meta-regressions

The covariates of interest for subgroup analyses and meta-regressions were:

  • Sex

  • Category of disease induction

  • Route of intervention administration

  • Whether the intervention was prophylactic or therapeutic (i.e. administered before or after disease model induction)

  • Duration of treatment period

  • The intervention administered

  • Dose of intervention

We also conducted subgroup analyses using (1) SyRCLE Risk of Bias and (2) ARRIVE reporting completeness assessment scores as covariates to evaluate their influence on effect size estimates. These were not specified in the study protocol, but evaluation of risk of bias is required for the Summary of Evidence table, and no studies were considered at low risk of bias or high reporting completeness to allow such a sensitivity analysis

The significance (p-value) reported is that for a test of whether the moderators are significantly different one from another, rather than whether the effect is significantly different from 0.

Sex

Figure 2.1.4.1 displays the estimates for the pooled SMDs when comparisons are stratified by sex of the animal. Whiskers indicate the 95% confidence interval of each estimate. The overall pooled SMD, not stratified by sex, is displayed as a diamond shape at the bottom of the plot.

Figure 2.1.4.1 - Effect of dopaminergic agent on Sucrose Preference by Sex

The p-value for the association between the sex of animal groups used and outcome reported was 0.2.

Level Number of categories for that level included in this analysis Attributable variance
Strain 10 0
Study x Strain 27 0.804
Study x Strain x Experiment 36 0

Category of disease induction

Figure 2.1.4.2 displays the estimates for the pooled SMDs when comparisons are stratified by the category of disease induction. Whiskers indicate the 95% confidence interval of each estimate. The overall pooled SMD, not stratified by category of disease induction, is displayed as a diamond shape at the bottom of the plot.

Figure 2.1.4.2 - Effect of dopaminergic agent on Sucrose Preference by category of disease induction

The p-value for the association between whether genetic or pharmacological models were used and outcome reported was 0.7.

Level Number of categories for that level included in this analysis Attributable variance
Strain 10 0
Study x Strain 27 0.978
Study x Strain x Experiment 36 0

Route of intervention administration

Figure 2.1.4.3 displays the estimates for the pooled SMDs when comparisons are stratified by the route of intervention administration. Whiskers indicate the 95% confidence interval of each estimate. The overall pooled SMD, not stratified by route of intervention administration, is displayed as a diamond shape at the bottom of the plot.

Figure 2.1.4.3 - Effect of dopaminergic agent on Sucrose Preference by Route of intervention administration

The p-value for the association between the route of intervention administration and outcome reported was 0.214.

Level Number of categories for that level included in this analysis Attributable variance
Strain 10 0
Study x Strain 27 0.567
Study x Strain x Experiment 36 0.011

Prophylactic or therapeutic intervention

Figure 2.1.4.4 displays the estimates for the pooled SMDs when comparisons are stratified by whether the intervention was administered prophylactically or therapeutically. Whiskers indicate the 95% confidence interval of each estimate. The overall pooled SMD, not stratified by whether the intervention was administered prophylactically or therapeutically, is displayed as a diamond shape at the bottom of the plot.

Figure 2.1.4.4 - Effect of dopaminergic agent on Sucrose Preference by prophylactic or therapeutic intervention

The p-value for the association between whether the intervention was administered prophylactically or therapeutically and outcome reported was 0.344.

Level Number of categories for that level included in this analysis Attributable variance
Strain 10 0
Study x Strain 27 0.846
Study x Strain x Experiment 36 0.009

Duration of treatment period

Figure 2.1.4.5 displays the estimates for the pooled SMDs when comparisons are stratified by the duration of treatment. Whiskers indicate the 95% confidence interval of each estimate. The overall pooled SMD, not stratified by duration of treatment, is displayed as a diamond shape at the bottom of the plot.

Figure 2.1.4.5 - Effect of dopaminergic agent on Sucrose Preference by duration of intervention

The p-value for the association between the duration of treatment and outcome reported was 0.565.

Level Number of categories for that level included in this analysis Attributable variance
Strain 10 0
Study x Strain 27 0.874
Study x Strain x Experiment 36 0.011

The intervention administered

Figure 2.1.4.6 displays the estimates for the pooled SMDs when comparisons are stratified by the intervention administered. Whiskers indicate the 95% confidence interval of each estimate. The overall pooled SMD, not stratified by the intervention administered, is displayed as a diamond shape at the bottom of the plot.

Figure 2.1.4.6 - Effect of dopaminergic agent on Sucrose Preference by intervention administered

The p-value for the association between the intervention administered and outcome reported was 0.591.

Level Number of categories for that level included in this analysis Attributable variance
Strain 10 6.76
Study x Strain 27 0.446
Study x Strain x Experiment 36 0.005

Dose of intervention

In this iteration of the review, the dopaminergic agents tested against control for their effect on Sucrose preference were: aripiprazole, pramipexole, buproprion, SKF83959, quinpirole, selegiline, P. orientalis seed, amantadine, piribedil, 2_HBC, D-amphetamine, L-DOPA, SKF38393, bromocriptine, cryptotanshinone, dopamine, ropinirole, simvastatin and tranylcypromine. Meta-regression using the administered dose as an explanatory variable was conducted for each drug where this had been reported in 10 or more experiments from 3 or more publications. No agent met these criteria.

SyRCLE RoB assessment considered as a categorical variable

Figure 2.1.4.7 displays the estimates for the pooled SMDs when comparisons are stratified by how many of the SyRCLE risk of bias assessment criteria (of which there are 10) that the experiment met. Whiskers indicate the 95% confidence interval of each estimate. The overall pooled SMD, not stratified by SyRCLE Risk of Bias, is displayed as a diamond shape at the bottom of the plot.

Figure 2.1.4.7 - Effect of dopaminergic agent on Sucrose Preference by SyRCLE RoB criteria met

The p-value for the association between SyRCLE Risk of Bias reporting and outcome reported was 0.876.

Level Number of categories for that level included in this analysis Attributable variance
Strain 10 0
Study x Strain 27 0.868
Study x Strain x Experiment 36 0.009

SyRCLE RoB assessment considering those studies where any item is at low risk of bias

Figure 2.1.4.8 displays the estimates for the pooled SMDs when comparisons are stratified by whether of not any of the SyRCLE Risk of bias domains were rated as low risk of bias. Whiskers indicate the 95% confidence interval of each estimate. The overall pooled SMD, not stratified by SyRCLE Risk of Bias, is displayed as a diamond shape at the bottom of the plot.

Figure 2.1.4.8 - effect of dopaminergic agent on Sucrose Preference by low SyRCLE RoB reporting

The p-value for the association between low SyRCLE Risk of Bias reporting and outcome reported was 0.876.

Level Number of categories for that level included in this analysis Attributable variance
Strain 10 0
Study x Strain 27 0.868
Study x Strain x Experiment 36 0.009

ARRIVE reporting guidelines performance

We provide a meta-regression where the number of ARRIVE items met is considered as a continuous variable.

Figure 2.1.4.9

The estimate for \(\beta\) was -0.015 (p = 0.894).

Level Number of categories for that level included in this analysis Attributable variance
Strain 10 0
Study x Strain 27 0.864
Study x Strain x Experiment 36 0.009

Heterogeneity explained by covariates (Dopaminergic agents and Sucrose preference)

The table below shows which of the covariates, if any, explain some of the heterogeneity observed in the effect sizes of the effect of dopaminergic agents on Sucrose preference. We present marginal R2, which measures the proportion of variance explained by including moderators in the model (the % change in the between-studies variance when the covariate is included in the model, in other words the % of the heterogeneity explained by the variable). The coefficients are derived form an RMA model fitted with an intercept (and so represent the point estimate and 95% CIs of the effect in each category).

Moderator Category \(\beta\) 95% CI Marginal R2 (%)
Overall effect - 1.335 0.878 to 1.792 -
Sex - - - 4.6%
- Female 0.454 -0.595 to 1.502 -
- Male 1.345 0.917 to 1.773 -
- Not reported NA NA to NA -
Category of disease model induction - - - 16.9%
- Behavioural early life stress 1.391 0.831 to 2.247 -
- Chronic unpredictable mild stress 0.998 -2.389 to 4.385 -
- Genetic models 1.345 -0.767 to 3.458 -
- Pharmacological early life stress 1.199 -2.212 to 4.611 -
- Pharmacological post weaning 2.158 -0.336 to 4.653 -
- Social or social defeat stress 0.532 -0.785 to 1.849 -
- Surgical models 2.434 0.666 to 4.202 -
Administration route - - - 23.3%
- Intraperitoneal 0.894 0.378 to 1.411 -
- Oral 1.879 1.206 to 2.553 -
- Other 1.207 0.234 to 2.18 -
- Subcutaneous 1.638 0.374 to 2.903 -
Prophylactic or therapeutic intervention - - - 4.2%
- Prophylactic 1.53 0.944 to 2.117 -
- Therapeutic 1.132 0.516 to 1.748 -
Duration of treatment period - - - 6%
- 1 to 4 weeks 1.564 0.948 to 2.18 -
- less than 1 week 0.956 -0.283 to 2.195 -
- 4 weeks or more 1.191 0.5 to 1.882 -
Intervention administered - - - 15.4%
- 2-HBC 2.541 -0.049 to 5.131 -
- amantadine 4.041 1.058 to 7.025 -
- aripiprazole 2.171 -0.399 to 4.741 -
- bromocriptine 1.454 -1.345 to 4.253 -
- buproprion 2.963 0.356 to 5.569 -
- cyrptotanshinone 0.848 -2.774 to 4.47 -
- dopamine 0.678 -2.496 to 3.852 -
- L-DOPA 2.494 -0.107 to 5.094 -
- P.orientalis seed 2.701 -0.147 to 5.549 -
- pramipexole 3.689 0.476 to 6.903 -
- quinpirole 1.546 -1.615 to 4.707 -
- ropinerole 0.396 -4.054 to 4.845 -
- selegiline 1.591 -0.977 to 4.16 -
- simvastatin 1.336 -2.049 to 4.72 -
- SKF38393 0.999 -33.48 to 35.477 -
- SKF83959 -0.034 -3.753 to 3.685 -
- tranylcypromine 4.016 1.011 to 7.021 -
Risk of Bias - - - 0.1%
- 0 criteria met 1.365 0.853 to 1.878 -
- 1 criteria met 1.294 0.511 to 2.077 -
Reporting completeness - - - 0.1%
- per unit increase -0.015 -0.253 to 0.222 -

2.1.5 Sensitivity Analyses

We examine the robustness of the findings for the primary outcome by performing the following sensitivity analyses

Imputed rho values of 0.2 and 0.8

In the previous analyses for the effect of dopaminergic agents on Sucrose preference, we imputed a \(\rho\) value - the imputed within-study correlation between observed effect sizes - of 0.5. Here, we examine the effect of imputing \(\rho\) values of 0.2 and 0.8.

When the \(\rho\) value is assumed to be 0.2, dopaminergic agents had a pooled effect on Sucrose preference of SMD = 1.49 (95% CI: 0.95 to 2.03) with a prediction interval of -1.08 to 4.06.

When the \(\rho\) value is assumed to be 0.8, dopaminergic agents had a pooled effect on Sucrose preference of SMD = 1.07 (95% CI: 0.46 to 1.68) with a prediction interval of -1.16 to 3.3.

For reference the pooled effect size when rho is assumed to be 0.5 is 1.34 (95% CI: 0.88 to 1.79).

NMD

For Sucrose preference, an NMD was calculable for 61 out of 64 comparisons, i.e. 95.31 % of comparisons.

The effect of administering a dopaminergic agent on Sucrose preference in animals using NMD as the effect size is shown in Figure 2.1.5. The pooled estimate for NMD across all individual comparisons is displayed as a diamond shape at the bottom of the plot. Dotted lines indicate the prediction interval of the pooled estimate.

Figure 2.1.5

Dopaminergic interventions had a pooled effect on Sucrose preference of NMD = 76.61 (95% CI: 58.8 to 94.42) with a prediction interval of -14 to 167.22). For reference the pooled effect size for SMD was (95% CI: to ).

61 experimental comparisons were reported in 35 experiments reported from 26 publications and involving 9 different animal strains.

Level Number of categories for that level included in this analysis Attributable variance
Strain 9 25.54
Study x Strain 26 967.09
Study x Strain x Experiment 35 491.77

2.1.6 Reporting bias/small-study effects

Because of the relationship between SMD effect sizes and variance inherent in their calculation, where study size is small the standard approach to seeking evidence of small-study effects (regression based tests including Egger’s regression test for multilevel meta-analysis) can lead to over-estimation of small-study effect (see for instance 10.7554/eLife.24260). To address this we used Egger’s regression test for multilevel meta-analysis, with regression of SMD effect size against 1/√N, where N is the total number of animals involved in an experiment.

Egger regression based on 64 studies of dopaminergic agents v Control where Sucrose preference was measured showed a coefficient for a small study effect of 15.22 (95% CI: 3.25 to 27.19; p = 0.014) in the context of a baseline estimate of effect of -2.44 (95% CI: -5.79 to 0.92; p = 0.133).

2.2 Outcome 2: Dopamine concentration

2.2.1 Risk of bias

Figure 2.2.1a shows the risk of bias summary for studies investigating the effect of administering a dopaminergic agent on dopamine concentrtaions in animals. The risk of bias assessment was performed using the SyRCLE’s RoB tool. Figure 2.2.1b shows the corresponding traffic light plot.

Figure 2.2.1

2.2.2 Reporting completeness

Figure 2.2.2a shows the reporting completeness summary for studies investigating the effect of administering a dopaminergic agent on dopamine concentrations in animals. The reporting completeness assessment was performed using the ARRIVE guidelines. Figure 2.2.2b shows the corresponding traffic light plot.

Figure 2.2.2

2.2.3 Meta-analysis

Multilevel analysis is only performed if there are 5 levels or more for at least one of Strain, Study and Experiment, and that is not the case here. 13 experimental comparisons were reported in 3 experiments reported from 3 publications and involving 2 different animal strains. We provide a conventional random effects model to illustrate the data. No subgroup analysis is performed.

2.3 Outcome 3: DOPAC concentration

This was only reported in 2 studies, so no further analysis will be performed.

2.4 Outcome 4: Dopamine / DOPAC ratio

This was only reported in 1 study, so no further analysis will be performed.

3 Effects of model induction

To provide context for the effects of dopaminergic agents described above, we also present findings from expriments where no therapeutic intervention was given, which have simply reported the effects on apical (sucrose preference test) and other (dopamine, DOPAC, Da/DOPAC ratio, dopamine receptor biology) of model induction. Modelling interventions comprise behavioural (31 experiments), pharmacological (9) and surgical (4) approaches.

28 studies (74 comparisons) investigated the effects of model induction. The number of studies and individual effect sizes for each outcome were:

* This outcome was identified in the study protocol as the primary outcome of interest.

3.1 Outcome 1: Sucrose preference

3.1.1 Risk of bias

Figure 3.1.1 shows the risk of bias summary for studies investigating the effect of modelling depression on sucrose preference in animals. The risk of bias assessment was performed using the SyRCLE RoB tool.

Figure 3.1.1

3.1.2 Reporting completeness

Figure 3.1.2 shows the reporting completeness summary for studies investigating the effect of modelling depression on sucrose preference in animals. The reporting completeness assessment was performed using the ARRIVE guidelines.

Figure 3.1.2

3.1.3 Meta-analysis

The effect of modelling depression on sucrose preference in animals using SMD as the effect size is shown in Figure 3.1.3. The pooled estimate for SMD across all individual comparisons is displayed as a diamond shape at the bottom of the plot. Dotted lines indicate the prediction interval (PrI) of the pooled estimate.

Figure 3.1.3

Depression modelling had a pooled effect on sucrose preference of SMD = -2.3 (95% CI: -3.15 to -1.45; 95% PrI: -6.57 to 1.96).

44 experimental comparisons were reported in 37 experiments reported from 28 publications and involving 9 different animal strains.

The following table structure is used throughout this report and is used to show the different levels contributing to that analysis, the number of unique categories in those levels, and the variance contributed by that level of analysis. Because levels are only included in the analysis where there are five or more unique categories, for some analyses the number of categories is 0, and the variance attributed to those levels in not applicable. Because the model is hierarchical, where for instance there are Studies which include different Strains, the number of categories for Study x Strain will exceed the number of Studies (by which we mean unique publications) referred to in the text.

Level Number of categories for that level included in this analysis Attributable variance
Strain 9 0
Study x Strain 28 3.25
Study x Strain x Experiment 37 0.03

3.1.4 Subgroup analyses and meta-regressions

The covariates of interest for subgroup analyses and meta-regressions were:

  • Sex

  • Method of disease induction

We also conducted subgroup analyses using (1) SyRCLE Risk of Bias and (2) ARRIVE reporting completeness assessment scores as covariates to evaluate their influence on effect size estimates. These were not specified in the study protocol, but evaluation of risk of bias is required for the Summary of Evidence table, and no studies were considered entirely at low risk of bias or of high reporting completeness to allow such a sensitivity analysis

The significance (p-value) reported is that for a test of whether the moderators are significantly different one from another, rather than whether the effect is significantly different from 0.

Sex

Figure 3.1.4.1 displays the estimates for the pooled SMDs when comparisons are stratified by sex of the animal. Whiskers indicate the 95% confidence interval of each estimate. The overall pooled SMD, not stratified by sex, is displayed as a diamond shape at the bottom of the plot.

Figure 3.1.4.1 - Effect of modelling depression on sucrose preference by sex

The p-value for the association between the sex of animal groups used and outcome reported was 0.087.

Level Number of categories for that level included in this analysis Attributable variance
Strain 9 0
Study x Strain 28 2.624
Study x Strain x Experiment 37 0

Category of disease induction

Figure 3.1.4.2 displays the estimates for the pooled SMDs when comparisons are stratified by the category of disease induction. Whiskers indicate the 95% confidence interval of each estimate. The overall pooled SMD, not stratified by category of disease induction, is displayed as a diamond shape at the bottom of the plot.

Figure 3.1.4.2 - Effect of modelling depression on sucrose preference by category of disease induction

The p-value for the association between the depression model used and the outcome reported was 0.64.

Level Number of categories for that level included in this analysis Attributable variance
Strain 9 0.068
Study x Strain 28 3.962
Study x Strain x Experiment 37 0.03

SyRCLE RoB assessment considered as a categorical variable

Figure 3.1.4.3 displays the estimates for the pooled SMDs when comparisons are stratified by how many of the SyRCLE risk of bias assessment criteria (of which there are 10) that the experiment met. Whiskers indicate the 95% confidence interval of each estimate. The overall pooled SMD, not stratified by SyRCLE Risk of Bias, is displayed as a diamond shape at the bottom of the plot.

Figure 3.1.4.3 - Effect of modelling depression on sucrose preference by SyRCLE RoB criteria met

The p-value for the association between SyRCLE Risk of Bias reporting and outcome reported was 0.002.

Level Number of categories for that level included in this analysis Attributable variance
Strain 9 0.171
Study x Strain 28 1.798
Study x Strain x Experiment 37 0.031

SyRCLE RoB assessment considering those studies where any item is at low risk of bias

Figure 3.1.4.4 displays the estimates for the pooled SMDs when comparisons are stratified by whether of not any of the SyRCLE Risk of bias domains were rated as low risk of bias. Whiskers indicate the 95% confidence interval of each estimate. The overall pooled SMD, not stratified by SyRCLE Risk of Bias, is displayed as a diamond shape at the bottom of the plot.

Figure 3.1.4.4 - Effect of modelling depression on sucrose preference by low SyRCLE RoB

The p-value for the association between low SyRCLE Risk of Bias reporting and outcome reported was 0.364.

Level Number of categories for that level included in this analysis Attributable variance
Strain 9 0
Study x Strain 28 3.508
Study x Strain x Experiment 37 0.031

ARRIVE reporting completeness guidelines

We provide a metaregression where the number of ARRIVE items met is considered as a continuous variable.

Figure 3.1.4.5

The p-value for the association between ARRIVE reporting completeness and outcome reported was 0.668.

Level Number of categories for that level included in this analysis Attributable variance
Strain 9 0
Study x Strain 28 3.456
Study x Strain x Experiment 37 0.032

Heterogeneity explained by covariates (Effect of modelling on Sucrose preference)

The table below shows which of the covariates, if any, explain some of the heterogeneity observed in the effect sizes of the effect of TAAR1 agonists on Sucrose preference. We present marginal R2, which measures the proportion of variance explained by including moderators in the model (the % change in the between-studies variance when the covariate is included in the model, in other words the % of the heterogeneity explained by the variable). The coefficients are derived form an RMA model fitted with an intercept (and so represent the point estimate and 95% CIs of the effect in each category).

Overall effect - -2.302 -3.151 to -1.452 -
Sex - - - 10.2%
- Female -1.406 -2.604 to -0.208 -
- Male -2.161 -2.852 to -1.471
- Not reported -5.504 -9.402 to -1.607
Category of disease model induction - - - 19.1%
- Behavioural early life stress -2.377 -3.401 to -0.806 -
- Chronic unpredictable mild stress -1.458 -8.023 to 5.108 -
- Pharmacological early life stress -1.554 -5.747 to 2.639 -
- Pharmacological post weaning -1.976 -6.371 to 2.418 -
- Social or social defeat stress -1.244 -3.756 to 1.268 -
- Surgical models -4.947 -8.338 to -1.556 -
Risk of Bias - - - 51.9%
- 0 criteria met -1.928 -2.747 to -1.109 -
- 1 criteria met -2.064 -3.171 to -0.956 -
Reporting completeness - - - 0.7%
- per unit increase 0.094 -0.352 to 0.54 -

3.1.5 Sensitivity Analyses

We examine the robustness of the findings for the primary outcome by performing the following sensitivity analyses

Imputed rho values of 0.2 and 0.8

In the previous analyses for the effect of depression modelling on sucrose preference, we imputed a \(\rho\) value - the imputed within-study correlation between observed effect sizes - of 0.5. Here, we examine the effect of imputing \(\rho\) values of 0.2 and 0.8.

When the \(\rho\) value is assumed to be 0.2, depression modelling had a pooled effect on sucrose preference of SMD = -2.3 (95% CI: -3.15 to -1.46) with a prediction interval of -6.57 to 1.96.

When the \(\rho\) value is assumed to be 0.8, depression modelling had a pooled effect on sucrose preference of SMD = -2.29 (95% CI: -3.14 to -1.44) with a prediction interval of -6.55 to 1.97.

For reference the pooled effect size when rho is assumed to be 0.5 is -2.3 (95% CI: -3.15 to -1.45), so it is robust to variations in the within-study correlations.

NMD

NMD analysis is not applicable to the analysis of the effects of disease modelling.

3.1.6 Reporting bias/small-study effects

Because of the relationship between SMD effect sizes and variance inherent in their calculation, where study size is small the standard approach to seeking evidence of small-study effects (regression based tests including Egger’s regression test for multilevel meta-analysis) can lead to over-estimation of small-study effect (see for instance 10.7554/eLife.24260). To address this we used Egger’s regression test for multilevel meta-analysis, with regression of SMD effect size against 1/√N, where N is the total number of animals involved in an experiment.

Egger regression based on 44 studies of modelling of depression where sucrose preference was measured showed a coefficient for a small study effect of -7.65 (95% CI: -31.18 to 15.89; p = 0.514).

3.2 Outcome 2: Dopamine concentrations

3.2.1 Risk of bias

Figure 3.2.1 shows the risk of bias traffic light plot for studies investigating the effect of modelling depression on dopamine concentrations in animals. The risk of bias assessment was performed using the SyRCLE RoB tool.

Figure 3.2.1

3.2.2 Reporting completeness

Figure 3.2.2 shows the traffic light plot for reporting completeness summary for studies investigating the effect of the modelling of depression on dopamine concentration in animals. The reporting completeness assessment was performed using the ARRIVE guidelines.

Figure 3.2.2

3.2.3 Meta-analysis

Multilevel analysis is only performed if there are 5 levels or more for at least one of Strain, Study and Experiment, and that is not the case here. 13 experimental comparisons were reported in 5 experiments reported from 5 publications and involving 3 different animal strains.

3.3 Outcome 3: DOPAC concentration

This was only reported in 2 studies, so no further analysis will be performed.

3.4 Outcome 4: Dopamine / DOPAC ratio

This was only reported in 1 study, so no further analysis will be performed.

3.5 Outcome 5: Dopamine receptor biology

This was only reported in 1 study, so no further analysis will be performed.

4. Observed relationships between different outcomes measures in the same cohorts of animals

We selected cohorts where at least one outcome was presented for at least two outcome types. Where there were two or more of the same outcome type within a cohort we calculated a standardised mean difference effect size for that outcome in that cohort, along with its standard error. Where there was a single effect size within a cohort we took the standard error of that effect size.

Then, for each pair of outcome measures we plotted the effect sizes for each cohort, and fitted a regression line weighted on the standard error in the outcome measure represented on the x-axis. Outcome measure pairs are coded according to whether they come from model induction studies (red, expectation of worsening anhedonia) or from intervention studies (green, expectation of improvement in anhedonia). The number of experimental comparisons observed from each cohort is reflected in the size of the symbol, and shown in the figure legend.

4.1 Relationship between change in Sucrose preference test and change in measured dopamine concentrations

4.2 Relationship between change in Sucrose preference test and change in measured dopamine / DOPAC ratio

4.3 Relationship between change in dopamine concentrations and change in DOPAC concentrations

4.4 Relationship between change in dopamine concentrations and change in dopamine / DOPAC ratio

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5. Attrition bias and adverse effects of treatment

2.62% of 953 animals in Control cohorts and 2.69% of 930 animals in Intervention cohorts ‘dropped out’ between allocation to group and outcome measurement. Given that 10 of 94 interventions (10.64%) were administered as a single dose, treatment emergent adverse effects likely to lead to withdrawal of an animal from the study would be unusual, and technical failure or attrition is more likely. This analysis is based on full reporting of animals excluded from analyses, and it may be that group sizes were specified ‘after the event’, or that there was unreported replacement of animals excluded during the experiment, so these data should be interpreted with caution.

6. Summary of the evidence

6.1 Dopaminergic agents versus control

Outcome Summary of the association Within-study biases Across-studies biases Indirectness Other biases
Sucrose preference 64 experimental comparisons from 37 experiments in 27 publications involving 10 animal strains and reporting data from 1156 animals; SMD = 1.33 (95% CI to 0.88 to 1.79; 95% PrI -0.76 to 3.43) (Section 3.1.3). No heterogeneity was observed. Moderate risk of bias likely to exaggerate the effects of dopaminergic agents. All studies had unclear risk of bias for most of the SyRCLE items. Reporting was mostly incomplete; the median number of ARRIVE items reported was 12 (of 22). Moderate risk of bias likely to exaggerate the effects of dopaminergic agents. No studies preregistered their analyses. There was evidence of small-study effects (Section 3.1.6). Moderate risk of indirectness. For explanation, see [1] below. No other risks identified.
Dopamine concentrations 13 experimental comparisons from 3 experiments in 3 publications involving 2 animal strains and reporting data from 228 animals. There were insufficient data to allow multilevel metargeression; conventional random effects meta-analysis gave SMD =1.63 (95% CI: 0.67 to 2.59; 95% PrI -1.69 to 4.95) (Section 3.2.3). We did not explore sources of heterogeneity. Moderate risk of bias likely to exaggerate the effects of dopaminergic agents. All studies had unclear risk of bias for most of the SyRCLE items. Reporting was mostly incomplete; the median number of ARRIVE items reported was 10 (of 22). Moderate risk of bias likely to exaggerate the effects of dopaminergic agents. No studies preregistered their analyses. We did not find evidence of small study effects. Moderate risk of indirectness. For explanation, see [2] below. No other risks identified.

6.2 Effect of inducing model, without treatment

To provide context for the effects of dopaminergic drugs in these models, we also present a summary of the effects of model induction.

Outcome Summary of the association Within-study biases Across-studies biases Indirectness Other biases
Sucrose preference 44 experimental comparisons from 37 experiments in 28 publications involving 9 animal strains and reporting data from 777 animals; SMD = -2.30 (95% CI: -3.51 to -1.45; 95% PrI -6.57 to 1.96). Moderate risk of bias likely to exaggerate the effects of anhedonia modelling. All studies had unclear risk of bias for most of the SyRCLE items. Reporting was mostly incomplete; the median number of ARRIVE items reported was 13 (of 22). Moderate risk of bias likely to exaggerate the effects of anhedonia modelling. No studies preregistered their analyses. There was no evidence for small-study effects. n.a. No other risks identified.
Dopamine concentrations 13 experimental comparisons from 5 experiments in 5 publications involving 3 animal strains and reporting data from 191 animals. There were insufficient data to allow multilevel metargeression; conventional random effects meta-analysis gave SMD =0.80 (95% CI: -2.05 to 0.45; 95% PrI -5.26 to 3.66) (Section 2.2.3). We did not explore sources of heterogeneity. The included study was at unclear risk of bias (SyRCLE); the number of ARRIVE items reported was 13 (of 22). Moderate risk of bias likely to exaggerate the effects of Dopaminergic agents. The study did not preregistered its analyses. n.a. No other risks identified.

Rationale for conclusions for indirectness: [1] Effect of dopaminergic agents on sucrose preference: Moderate risk of indirectness We had concerns for indirectness because all experiments were in rodents, and beacuse anhedonia (evaluated using the sucrose preference test) was not identified in the JLA depression Priority Setting Partnership ‘Top 10’. However, anhedonia is a well recognised feature of human disease.There were a range of models used including pharmacological, behavioural and ‘surgical’ (modelling stroke or traumatic brain injury) which are each related to the causation or triggering of depression in humans, and some of these models recapitulate the change in hippocampal volume observed in human depression. Known antidepressants have been reported to increase sucrose preference in animal models of depression, and the depressive phenotype of the WAG/RiJ rat is responsive to antidepressant medication.

[2] Effect of dopaminergic agents on dopamine concentrations: Moderate risk of indirectness In addition to the concerns under [1] above, the concentration of dopamine is not a clinical endpoint, so is therefore less direct.

Evaluation of indirectness of evidence (based on criteria in document “Assessing the certainty of evidence in animal studies”) for the studies included in the review

The framework for the evaluation of indirectness is based on eight dimensions, based on the work of Belzung and Lemoine, and comprising (i) Homological validity - what is the extent of homology between the model organism and humans relevant to the condition studied; (ii) Ontopathogenic validity - Does the model include prenatal or early life exposures inducing transition from initial organism to vulnerable organism; (iii) Triggering validity - are any triggering factors used in the modelling – or their homologues -known to induce psychosis or relapse in humans?; (iv) Mechanistic validity - whether the neurobiological or cognitive mechanisms which operate in human disease can be observed in the animal model; (v) Induction validity - Does the induction of the disease model induce changes in biomarkers (see below) which are known to be altered in human disease?; (vi) Remission validity - What is the effect of other drugs known to be effective in humans in the particular animal model / outcome measure pair? ; (vii) Biomarker validity - are changes in disease markers (eg neurotransmitter levels, structural brain imaging) seen in human disease also seen in this animal model?; and (viii) Ethological validity - what is the ‘behavioural distance’ between the model phenotype in animals and the symptoms and signs of human disease at which treatment is targeted?

Dimension Characteristic Homological validity Ontopathogenic validity Triggering validity Mechanistic validity Induction validity Remission validity Biomarker validity Ethological validity
Species and strain Rat, Mouse We could find no evidence that the rat behavioural repertoire is closer to human than is the mouse n.a. n.a. n.a. n.a. n.a. n.a. n.a.
Model Induction Models using genetic induction – the WAG Riij model The WAG/RiJ rat is an inbred strain which manifests features of absence epilepsy and comorbid depression. No n.a. Rats manifest abnomalities in DA-ergic and 5HT systems similar to those seen in depression n.a. Known antidepressant drugs improve depressive behaviours in WAG/Rj rats n.a. n.a.
~ Pharmacological models (Tetrabenazine) n.a. No NA Tetrabenazine depletes central dopamine stores Tetrabenazine causes depressive symptomatology in humans NA NA n.a.
NA Behavioural Models n.a. exposure to adversity in early life is associated with depression in adulthood exposure to adversity is known to trigger episodes of depression NA NA NA hippocampal volume is reduced in CUMS and in human depression NA
NA Surgical Models n.a. No The models used were of stroke (MCAO) combined with spatial restraint stress; and of traumatic brain injury. In humans, both of these are associated with depression. NA considered’multi-factorial; may be a general effect of adversity n.a. hippocampal volume is reduced following experimental TBI; no evidence in MCAO other than direct effect of infact NA
Outcome Measure Sucrose preference test n.a. n.a. n.a. n.a. n.a. Desmethylimipramine increases sucrose preference in chronic unpredictable mild stress (10.1007/BF00187257) n.a. Anhedonia is not listed on the JLA depression PSP top 10, and so the ethological validity of these measures as relevant to unmet clinical need is uncertain
~ Dopamine concentration n.a. n.a. n.a. reduced [DA] is argued to lead to the reduced dopamine transporter levels reported in human depression DA depletion causes depression in humans CUMS increases [DA] in nucleus accumbens, and this is reversed by fluoxetine n.a. NA

The description of the criteria is available at https://doi.org/10.17605/OSF.IO/TDMAU

Evaluation of the concordance between different outcome measures

For both the induction of the disease model and the effects of dopaminergic interventions, there was some agreement between the effect sizes measured using these different outcomes when applied to the same cohort of animals. The data are however too sparse to allow firm conclusions at the level of outcome measure pairs.

7. Software used

We used R version 4.3.1 (R Core Team 2023) and the following R packages: devtools v. 2.4.5 (Wickham et al. 2022), dosresmeta v. 2.0.1 (Crippa and Orsini 2016), ggpubr v. 0.6.0 (Kassambara 2023), gtools v. 3.9.5 (Warnes et al. 2023), Hmisc v. 5.1.1 (Harrell Jr 2023a), kableExtra v. 1.4.0.3 (Zhu 2024), knitr v. 1.45 (Xie 2014, 2015, 2023), Matrix v. 1.6.5 (Bates, Maechler, and Jagan 2024), meta v. 7.0.0 (Balduzzi, Rücker, and Schwarzer 2019), metadat v. 1.2.0 (White et al. 2022), metafor v. 4.4.0 (Viechtbauer 2010), mvmeta v. 1.0.3 (Gasparrini, Armstrong, and Kenward 2012), numDeriv v. 2016.8.1.1 (Gilbert and Varadhan 2019), orchaRd v. 2.0 (Nakagawa et al. 2023), patchwork v. 1.2.0 (Pedersen 2024), PRISMA2020 v. 1.1.1 (Haddaway et al. 2022), rje v. 1.12.1 (Evans 2022), rms v. 6.7.1 (Harrell Jr 2023b), robvis v. 0.3.0.900 (McGuinness and Higgins 2020), tidyverse v. 2.0.0 (Wickham et al. 2019), usethis v. 2.2.3 (Wickham et al. 2024), xtable v. 1.8.4 (Dahl et al. 2019).

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